Programmed Death-Ligand 1 Copy Number Loss in NSCLC Associates With Reduced Programmed Death-Ligand 1 Tumor Staining and a Cold Immunophenotype

Could Programmed Death-Ligand 1 Copy Number Alterations be a Predictive Biomarker for Immunotherapy Response?

“…Expression levels of inflammatory mediators (interferon-g, interleukin [IL]-6, IL-1, matrix metalloproteinase-9) and immunosuppressive mediators (IL-10, transforming growth factor-b) were used as surrogate markers of an immunologically cold tumor microenvironment. 24 They found that PD-L1 copy number loss was associated with reduced expression of these inflammatory mediators, however there is no clinical response or survival outcomes data reported. The data suggests that a low PD-L1 copy number could be further developed to be a biomarker for a less inflammatory TIME and therefore predict a lack of response to anti-PD therapy.…”

“…22 Finally, PD-L1 copy number gains are associated with PD-L1 protein positivity in many solid tumors including NSCLC. 22,23 In this issue of the Journal of Thoracic Oncology, Bozinovski et al 24 investigated tumor PD-L1 copy number alterations, as measured by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), as a possible biomarker that could be used to supplement PD-L1 IHC staining as a predictor of response to anti-PD therapy. Using surgical samples of tumor and normal adjacent lung parenchyma tissue, investigators measured PD-L1 gene copy number and mRNA expression by RT-qPCR.…”

“…The data suggests that a low PD-L1 copy number could be further developed to be a biomarker for a less inflammatory TIME and therefore predict a lack of response to anti-PD therapy. 24 To date, there has been one published study evaluating the relationship between PD-L1 copy number and response to immunotherapy. Inoue et al 25 evaluated PD-L1 copy number, measured by fluorescence in situ hybridization in 200 patients with advanced NSCLC who were treated with nivolumab.…”

“…22,25 In the Bozinovski study, 17% of NSCLC tumors were found to have a copy number loss whereas 7% had a copy number gain, thus, providing actionable data on only a quarter of potential patients if copy number alterations were to be used as a predictive biomarker. 24 The Bozinovski study also evaluates PD-L1 copy number alterations in tissue obtained from bronchoscopic needle biopsies and compares variation in PD-L1 copy number and PD-L1 mRNA expression within multiple samples from the same patient's primary tumor and metastatic lymph node tissue and between different lymph nodes using RT-qPCR. 24 The authors observed a close correlation between PD-L1 tumor proportion score by IHC and PD-L1 mRNA expression.…”

“…24 The Bozinovski study also evaluates PD-L1 copy number alterations in tissue obtained from bronchoscopic needle biopsies and compares variation in PD-L1 copy number and PD-L1 mRNA expression within multiple samples from the same patient's primary tumor and metastatic lymph node tissue and between different lymph nodes using RT-qPCR. 24 The authors observed a close correlation between PD-L1 tumor proportion score by IHC and PD-L1 mRNA expression. In addition, they found that there was less heterogeneity in PD-L1 copy number across multiple biopsy sites than PD-L1 mRNA expression, 24 suggesting that PD-L1 copy number might serve as a more reliable biomarker than PD-L1 staining or PD-L1 mRNA expression.…”